Lysosomes are membrane-bound cell organelles central to degradation processes in animal cells. Extracellular materials such as microorganisms taken up by phagocytosis, macromolecules by endocytosis, and unwanted cell organelles, fuse with lysosomes and are broken down to their basic molecules. Thus, lysosomes are the recycling units of a cell. Lysosomes are also responsible for cellular homeostasis for their role in secretion, plasma membrane repair, cell signaling, and energy metabolism.
The essential role of lysosomes in cellular degradation processes puts these organelles at the crossroads of several cellular processes, with significant implications for health and disease. Defects in one of 60 lysosomal enzymes, transmembrane proteins or other components of this organelle, prevent the breakdown of target molecules, and are responsible for more than 60 different human genetic diseases, which are collectively known as lysosomal storage disorders. The large number and variety of human pathological conditions that are characterized, if not caused by aberrant lysosomal functions, underscores the critical importance of the autophagy-lysosome pathways to cellular metabolism. In these diseases as well as diseases characterized by lysosomal dysfunction, undegraded materials accumulate within the lysosomes, contributing to the presence or severity of disease ranging from lysosomal storage disorders to neurodegenerative diseases, to cancer, to cardiovascular disease. For instance, the neuronal ceroid lipofuscinoses (NCLs), lysosomal storage disorders also known as Batten disease, are a group of neurodegenerative disorders considered the most common of the neurogenetic storage diseases, with a prevalence of 1 in 12,500 in some populations. There are currently no cures or approved treatments for any of the 14 forms of Batten disease.
The inventors have previously discovered that the cellular clearance pathways are coordinated by an integrated control system named the CLEAR gene network (Coordinated Lysosomal Expression and Regulation), whose master transcriptional regulator is TFEB. However, the in vivo pathways regulating TFEB and the CLEAR network were not sufficiently understood, making drug development for treating such diseases challenging. For instance, no cures or approved treatments targeting TFEB currently exist. Additionally, while clinical trials are in progress on possible treatments for some of these diseases, there is currently no approved treatment for the majority of lysosomal storage disorders or many disorders characterized by lysosomal dysfunction.
Therefore, there is a need in the art for compositions and methods of treating lysosomal storage disorders and disorders characterized by lysosomal dysfunction based on an enhancement of lysosomal clearance and the removal of cellular aggregates.